Hypoxia-inducible factors individually facilitate inflammatory myeloid metabolism and inefficient cardiac repair

J Exp Med. 2021 Sep 6;218(9):e20200667. doi: 10.1084/jem.20200667. Epub 2021 Jul 29.

Abstract

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cardiomyopathies / physiopathology
  • Disease Models, Animal
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Myeloid Cells / metabolism*
  • Myeloid Cells / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Ischemia / physiopathology
  • Myocarditis / metabolism
  • Myocarditis / pathology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • endothelial PAS domain-containing protein 1